- Susceptibility to systemic lupus erythematosus (SLE) is inherited as a complex multigenic trait with the added complication of gene heterogeneity. To define the genetics of this disease, the principal investigator and others have taken advantage of the uniform genetic composition of inbred mouse strains, of which several spontaneously develop clinical and immunopathologic characteristics similar to human SLE. In the previous funding period, the chromosomal locations of autoimmune susceptibility loci for the four main lupus strains (NZB, NZW, BXSB, and MRL-Fas-lpr) were identified. These studies demonstrated a multiplicative threshold inheritance of disease traits, and that loci contribute to specific immunopathologic stages, in many instances beyond autoantibody production. Among the loci identified, four (Lmb 1 to 4) from the MRL-Fas-lpr x C57BL/6-Fas-lpr cross were significantly linked to traits with the highest likelihoods. This proposal focuses on the MRL-Fas-lpr and C57BL/6-Fas-lpr strains to define the contributions and identities of genes associated with susceptibility loci. Loci for two important traits with weaker linkages, glomerulonephritis and arthritis, will be more definitively mapped by combining additional (MRL-Fas-lpr x C57BL/6-Fas-lpr) F2 intercross mice to the previous set which they have studied. To determine the contributions, modes of inheritance, and interactions of susceptibility genes, congenic and derivative mice for these and the four Lmb loci will be generated and analyzed for autoimmune traits. Fine mapping will be performed using crosses of congenic mice and cloning of genes corresponding to susceptibility loci will be carried out by screening candidate genes or, if necessary, by physical cloning. Findings generated from these studies, they expect, will significantly enhance efforts to define the etiopathogenesis of autoimmunity, and may lead to new approaches in the diagnosis and therapy of human SLE.